Jack A. Tuszynski

Kinklike excitations as an energy-transfer mechanism in microtubules

A model is presented which is intended to provide a realistic physical picture of the energy transfer mechanism in cell microtubles (MT). A classical φ4-model in the presence of a constant electric field is used as a conceptual basis. It is demonstrated that if kink-like excitations arise as a result of GTP hydrolysis then an intrinsic electrical force may cause them to propagate along the microtuble. A discussion is given on the possible effects on these excitations on the dynamics of microtubles.

A Unique Mode of Microtubule Stabilization Induced by Peloruside A

Microtubules are significant therapeutic targets for the treatment of cancer, where suppression of microtubule dynamicity by drugs such as paclitaxel forms the basis of clinical efficacy. Peloruside A, a macrolide isolated from New Zealand marine sponge Mycale hentscheli, is a microtubule-stabilizing agent that synergizes with taxoid drugs through a unique site and is an attractive lead compound in the development of combination therapies. We report here unique allosteric properties of microtubule stabilization via peloruside A and present a structural model of the peloruside-binding site. Using a strategy involving comparative hydrogen-deuterium exchange mass spectrometry of different microtubule-stabilizing agents, we suggest that taxoid-site ligands epothilone A and docetaxel stabilize microtubules primarily through improved longitudinal interactions centered on the interdimer interface, with no observable contributions from lateral interactions between protofilaments. The mode by which peloruside A achieves microtubule stabilization also involves the interdimer interface, but includes contributions from the alpha/beta-tubulin intradimer interface and protofilament contacts, both in the form of destabilizations. Using data-directed molecular docking simulations, we propose that peloruside A binds within a pocket on the exterior of beta-tubulin at a previously unknown ligand site, rather than on alpha-tubulin as suggested in earlier studies.

Cancer proliferation and therapy: the Warburg effect and quantum metabolism

BackgroundMost cancer cells, in contrast to normal differentiated cells, rely on aerobic glycolysis instead of oxidative phosphorylation to generate metabolic energy, a phenomenon called the Warburg effect.ModelQuantum metabolism is an analytic theory of metabolic regulation which exploits the methodology of quantum mechanics to derive allometric rules relating cellular metabolic rate and cell size. This theory explains differences in the metabolic rates of cells utilizing OxPhos and cells utilizing glycolysis. This article appeals to an analytic relation between metabolic rate and evolutionary entropy - a demographic measure of Darwinian fitness - to: (a) provide an evolutionary rationale for the Warburg effect, and (b) propose methods based on entropic principles of natural selection for regulating the incidence of OxPhos and glycolysis in cancer cells.ConclusionThe regulatory interventions proposed on the basis of quantum metabolism have applications in therapeutic strategies to combat cancer. These procedures, based on metabolic regulation, are non-invasive, and complement the standard therapeutic methods involving radiation and chemotherapy

A nonlinear model of ionic wave propagation along microtubules

Microtubules (MTs) are important cytoskeletal polymers engaged in a number of specific cellular activities including the traffic of organelles using motor proteins, cellular architecture and motility, cell division and a possible participation in information processing within neuronal functioning. How MTs operate and process electrical information is still largely unknown. In this paper we investigate the conditions enabling MTs to act as electrical transmission lines for ion flows along their lengths. We introduce a model in which each tubulin dimer is viewed as an electric element with a capacitive, inductive and resistive characteristics arising due to polyelectrolyte nature of MTs. Based on Kirchhoff’s laws taken in the continuum limit, a nonlinear partial differential equation is derived and analyzed. We demonstrate that it can be used to describe the electrostatic potential coupled to the propagating localized ionic waves.

Molecular dynamics modeling of tubulin C‐terminal tail interactions with the microtubule surface

Tubulin, an α/β heterodimer, has had most of its 3D structure analyzed; however, the carboxy (C)‐termini remain elusive. Importantly, the C‐termini play critical roles in regulating microtubule structure and function. They are sites of most of the post‐translational modifications of tubulin and interaction sites with molecular motors and microtubule‐associated proteins. Simulated annealing was used in our molecular dynamics modeling to predict the interactions of the C‐terminal tails with the tubulin dimer. We examined differences in their flexibility, interactions with the body of tubulin, and the existence of structural motifs. We found that the α‐tubulin tail interacts with the H11 helix of β‐tubulin, and the β‐tubulin tail interacts with the H11 helix of α‐tubulin. Tail domains and H10/B9 loops interact with each other and compete for interactions with positively‐charged residues of the H11 helix on the neighboring monomer. In a simulation in which α‐tubulins H10/B9 loop switches on sub‐nanosecond intervals between interactions with the C‐terminal tail of α‐tubulin and the H11 helix of β‐tubulin, the intermediate domain of α‐tubulin showed more fluctuations compared to those in the other simulations, indicating that tail domains may cause shifts in the position of this domain. This suggests that C‐termini may affect the conformation of the tubulin dimer which may explain their essential function in microtubule formation and effects on ligand binding to microtubules. Our modeling also provides evidence for a disordered‐helical/helical double‐state system of the T3/H3 region of the microtubule, which could be linked to depolymerization following GTP hydrolysis. Proteins 2011;

A nonlinear cable-like model of amplified ionic wave propagation along microtubules

The properties of ionic waves propagating along a microtubule in solution are analyzed in this paper. We derive the constitutive equations in the continuum limit, obtain appropriate parameter values from the tubulin structural data and solve numerically these equations finding their dependence on the range of parameter values. Possible biophysical implications of the results that may arise from the model are discussed.

Identification of tubulin drug binding sites and prediction of relative differences in binding affinities to tubulin isotypes using digital signal processing

Microtubules are involved in numerous cellular processes including chromosome segregation during mitosis and, as a result, their constituent protein, tubulin, has become a successful target of several chemotherapeutic drugs. In general, these drugs bind indiscriminately to tubulin within both cancerous and healthy cells, resulting in unwanted side effects. However, differences between beta-tubulin isotypes expressed in a wide range of cell types may aid in the development of anti-tubulin drugs having increased specificity for only certain types of cells. Here, we describe a digital signal processing (DSP) method that is capable of predicting hot spots for the tubulin family of proteins as well as determining relative differences in binding affinities to these hot spots based only on the primary sequence of 10 human tubulin isotypes. Due to the fact that several drug binding sites have already been characterized within beta-tubulin, we are able to correlate hot spots with the binding sites for known chemotherapy drugs. We have also verified the accuracy of this method using the correlation between the binding affinities of characterized drugs and the tubulin isotypes. Additionally, the DSP method enables the rapid estimation of relative differences in binding affinities within the binding sites of tubulin isotypes that are yet to be experimentally determined.

The enigma of microtubules and their self-organizing behavior in the cytoskeleton

The cytoskeleton of eukaryotic cells contains networks of protein polymers called microtubules which structurally and functionally organize their interiors. Both in vivo and in vitro microtubules exhibit a fascinating and yet poorly understood array of important functions involving complex self-organization phenomena which are very sensitive to physiological and laboratory conditions, respectively. In this paper we discuss the main physical characteristics of microtubules focusing our attention on four particular aspects: (a) the dynamics of their assembly and disassembly processes (b) the types and the range of existence of ordered dipolar phases and (c) modes of energy transfer and (d) information processing capabilities.

Electrodynamics of microtubular motors: the building blocks of a new model

Microtubules are ubiquitous components of the cytoskeleton. They participate in many motility processes ranging from intracellular transport or chromosome movement during mitosis to ciliary and flagellar beating. The biophysical mechanism inherent in the generation and control of movement in all these motility phenomena has not yet been entirely elucidated. The authors propose a new model based on a charge transfer mechanism capable of shedding a new light on the molecular foundations of all motility processes. Electron transfer along the microtubular lattice is responsible for activation and control of all microtubule-associated ATPases (i.e. force generating enzymes). Microtubules are thus shown to be the basic motors of cell dynamics. The model is first applied to intracellular transport and ciliary and flagellar beating. Through two additional examples, the authors show the heuristic capabilities of the suggested hypothesis. The application of charge transfer control to the Protozoan Euglena gracilis leads to a plausible model capable of accounting for its phototactic response mechanism. Furthermore, the model allows a new interpretation of the electrophysiological response in vertebrate photoreceptors.

Emergence of power laws in the pharmacokinetics of paclitaxel due to competing saturable processes.

PURPOSE This study presents the results of power law analysis applied to the pharmacokinetics of paclitaxel. Emphasis is placed on the role that the power exponent can play in the investigation and quantification of nonlinear pharmacokinetics and the elucidation of the underlying physiological processes. METHODS Forty-one sets of concentration-time data were inferred from 20 published clinical trial studies, and 8 sets of area-under-the-curve (AUC) and maximum concentration (Cmax) values as a function of dose were collected. Both types of data were tested for a power law relationship using least squares regression analysis. RESULTS Thirty-nine of the concentration-time curves were found to exhibit power law tails, and two dominant fractional exponents emerged. Short infusion times led to asymptotic tails with a single power exponent of - 1.57 +/- 0.14, while long infusion times resulted in steeper tails characterized by roughly twice the exponent. The curves following intermediate infusion times were characterized by two consecutive power laws; an initial short slope with the larger alpha value was followed by a crossover to a long-time tail characterized by the smaller Beta exponent. The AUC and Cmax parameters exhibited a power law dependence on the dose, with fractional power exponents that agreed with each other and with the exponent characterizing the shallow decline. Computer simulations revealed that a two- or three-compartment model with both saturable distribution and saturable elimination can produce the observed behaviour. Analogous linear models did not provide good fits over the range of values collected empirically. Furthermore, there is preliminary evidence that the nonlinear dose-dependence is correlated with the power law tails. CONCLUSIONS Assessment of data from published clinical trials suggests that power laws accurately describe the concentration-time curves and nonlinear dose-dependence of paclitaxel, and the power exponents provide new\ insights into the underlying drug mechanisms. The interplay between two saturable processes can produce a wide range of behaviour, including concentration-time curves with exponential, power law, and dual power law tails.